Celiac disease is an autoimmune disease driven by an immune response to gluten peptides. The disease is strongly associated with the MHC class II molecule HLA-DQ2.5. The similar molecule HLA-DQ2.2 is not associated with celiac disease. The two molecules have very similar peptide binding domains and are both able to bind gluten T-cell epitopes. A marked difference in CLIP presentation at the peptide binding groove has been observed between the two HLA molecules. HLA-DQ2.5 presents large amounts of CLIP peptides in the binding groove, while HLA-DQ2.2 does not. There are only 10 polymorphic residues in the membrane distal domains of these HLA- molecules. This thesis is part of a large study using site-directed mutagenesis, flow cytometry and mass spectrometry to clarify which, if any, of these polymorphic residues are responsible for the difference seen in CLIP presentation and stability.
This investigation may also elucidate part of the differences seen in celiac disease association. Results from parts of the study have been published by Fallang.et.al.1 showing that the polymorphism in position α22 is of great importance for the presentation and stability of CLIP and other peptides bound to HLA-DQ2.2 and HLA-DQ2.5.
Findings presented in this thesis show that the polymorphisms in positions α31, α37 and α72 also have an effect on CLIP presentation and stability in HLA-DQ2.5 and HLA-DQ2.2. Their effect appears to be the opposite of the one described in the previous study, and may help explain some of the results presented there.